5-Phenylthiazole derivatives and their use as p13 kinase inhibitors

ABSTRACT

Compounds of formula I 
                         
in free or salt form, wherein R 1 , R 2 , R 3 , R 4  and R 5  have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

The present invention relates to organic compounds, their preparationand their use as pharmaceuticals.

In a first aspect, the present invention provides compounds of formula I

in free or salt form, whereinR¹ is a 5 or 6-membered heterocyclic ring containing nitrogen andoptionally one or more further hetero atoms selected from the groupconsisting of nitrogen, oxygen and sulphur,that ring being optionally substituted by halo, C₁-C₈-alkyl optionallysubstituted by —NR⁶R⁷, carboxy, C₁-C₈-alkoxycarbonyl or a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur,C₁-C₈-alkoxy, —NR⁶R⁷, C₃-C₈-cycloalkyl optionally substituted bycarboxy, or a 5 or 6-membered heterocyclic ring containing at least onehetero atom selected from the group consisting of nitrogen and oxygen,that ring being optionally substituted by C₁-C₈-alkyl;R² is C₁-C₈-alkyl or halo;R³ is hydroxy, halo, C₁-C₈-alkoxy, C₁-C₈-alkylcarbonyl, —SO₂NR⁸R⁹,—SOR¹⁰ or —SO₂R¹¹, carboxy, aminocarbonyl, di(C₁-C₈-alkyl)aminocarbonyl,—NO₂ or cyano and is in the para or meta position with respect to theindicated thiazole ring;R⁴ and R⁵ are each independently hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxyoptionally substituted by a 5 or 6-membered heterocyclic ring containingat least one hetero atom selected from the group consisting of nitrogen,oxygen and sulphur, halo, halo-C₁-C₈-alkyl, cyano, —SO₂NH₂, carboxy,amino, amino-C₁-C₈-alkyl, di(C₁-C₈-alkyl)amino-C₁-C₈-alkyl,amino-C₁-C₈-alkoxy, di(C₁-C₈-alkyl)amino-C₁-C₈-alkoxy, aminocarbonyl,C₁-C₈-alkylaminocarbonyl, di(C₁-C₈-alkyl)aminocarbonyl, —NR¹²R¹³,carboxy-C₁-C₈-alkyl, carboxy-C₁-C₈-alkoxy, R¹⁴, —OR¹⁴ or a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl;R⁶ is hydrogen or C₁-C₈-alkyl;R⁷ is C₁-C₈-alkyl optionally substituted by hydroxy, C₁-C₈-alkoxy,di(C₁-C₈-alkyl)amino or a 5 or 6-membered heterocyclic ring containingat least one hetero atom selected from the group consisting of nitrogen,oxygen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl;R⁸ is hydrogen or C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, cyano, amino, C₁-C₈-alkylamino, di(C₁-C₈-alkyl)amino or a5 or 6-membered heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl;R⁹ is hydrogen, C₁-C₈-alkyl optionally substituted by hydroxy, orC₃-C₈-cycloalkyl;R¹⁰ is C₁-C₈-alkyl;R¹¹ is C₁-C₈-alkyl optionally substituted by halogen, hydroxy,C₁-C₈-alkoxy, cyano, amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino;R¹² is hydrogen or C₁-C₈-alkyl;R¹³ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl optionally substituted byhydroxy, amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino or R¹² and R¹³together with the nitrogen atom to which they are attached form a 5 or6-membered saturated or unsaturated heterocyclic ring that contains oneor more further hetero atoms selected from the group consisting ofoxygen, nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl; andR¹⁴ is C₁-C₈-alkyl optionally substituted by hydroxy or —NR¹²R¹³.

Terms used in the specification have the following meanings:

“Optionally substituted” as used herein means the group referred to canbe substituted at one or more positions by any one or any combination ofthe radicals listed thereafter.

“C₁-C₈-alkyl” denotes straight chain or branched alkyl having 1 to 8carbon atoms. Preferably, C₁-C₈-alkyl is C₁-C₄-alkyl.

“C₃-C₈-cycloalkyl” denotes cycloalkyl having 3 to 8 ring carbon atoms,for example a monocyclic group such as a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any of which can besubstituted by one or more, usually one or two, C₁-C₄-alkyl groups, or abicyclic group such as bicycloheptyl or bicyclooctyl.

Preferably “C₃-C₈-cycloalkyl” is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl.

“C₁-C₈-alkoxy” denotes straight chain or branched alkoxy having 1 to 8carbon atoms. Preferably, C₁-C₈-alkoxy is C₁-C₄-alkoxy.

“Halogen” or “halo” may be fluorine, chlorine, bromine or iodine;preferably it is fluorine or chlorine.

“C₁-C₈-haloalkyl” denotes C₁-C₈-alkyl as hereinbefore definedsubstituted by one or more halogen atoms, preferably one, two or threehalogen atoms, preferably fluorine or chlorine atoms. PreferablyC₁-C₈-haloalkyl is C₁-C₄-alkyl substituted by one, two or three fluorineor chlorine atoms.

“C₁-C₈-alkylcarbonyl” denotes C₁-C₈-alkyl as hereinbefore definedattached by a carbon atom to a carbonyl group.

“C₁-C₈-alkylamino” and “di(C₁-C₈-alkyl)amino” denote amino substitutedrespectively by one or two C₁-C₈-alkyl groups as hereinbefore defined,which may be the same or different. Preferably C₁-C₈-alkylamino anddi(C₁-C₈-alkyl)amino are respectively C₁-C₄-alkylamino anddi(C₁-C₄-alkyl)amino.

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

R¹ may be, for example, pyrrole, pyrazole, imidazole, triazole,tetrazole, thiadiazole, oxazole, isoxazole, isothiazole, oxadiazole,pyridine, oxazole, pyrazine, pyridazine, pyrimidine, piperazine,morpholino, triazine, oxazine or thiazole. However R¹ is preferably anaromatic heterocyclic ring, especially pyrazine, pyridazine orpyrimidine. The heterocyclic ring may be substituted by one or more,e.g. one or two, specific optional halo, C₁-C₈-alkyl, C₁-C₈-alkoxy,NR⁶R⁷ substituents.

Where the heterocyclic ring is substituted by a further 5 or 6-memberedheterocyclic ring this ring may be, for example, pyrrole, pyrazole,imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole,oxadiazole, pyridine, oxazole, pyrazine, pyridazine, pyrimidine,piperazine, morpholino, triazine, oxazine or thiazole, but it ispreferably a saturated ring, especially piperazine or morpholino,optionally substituted by one or two C₁-C₈-alkyl groups.

Where R¹ is substituted by C₁-C₈-alkyl substituted by a 5 or 6-memberedheterocyclic ring containing at least one ring hetero atom selected fromthe group consisting of nitrogen, oxygen and sulphur this ring may be,for example, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole,isoxazole, isothiazole, oxadiazole, pyridine, oxazole, pyrazine,pyridazine, pyrimidine, piperazine, morpholino, triazine, oxazine orthiazole, but it is preferably morpholino or piperazine.

Where R⁴ or R⁵ is C₁-C₈-alkoxy substituted by a 5 or 6-memberedheterocyclic ring containing at least one ring hetero atom selected fromthe group consisting of nitrogen, oxygen and sulphur this ring may be,for example, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole,isoxazole, isothiazole, oxadiazole, pyridine, oxazole, pyrazine,pyridazine, pyrimidine, piperazine, morpholino, triazine, oxazine orthiazole, but it is preferably morpholino.

Where R⁴ or R⁵ is a 5 or 6-membered heterocyclic ring containing atleast one ring hetero atom selected from the group consisting ofnitrogen, oxygen and sulphur this ring may be, for example, pyrrole,pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole,isothiazole, oxadiazole, pyridine, oxazole, pyrazine, pyridazine,pyrimidine, piperazine, morpholino, triazine, oxazine or thiazole, butit is preferably imidazole or piperazine, and that ring is preferablysubstituted by C₁-C₈-alkyl, especially C₁-C₄-alkyl.

Preferred compounds of the present invention include compounds offormula I, in free or salt form, wherein

R¹ is a 5 or 6-membered heterocyclic ring containing nitrogen andoptionally one or more further hetero atoms selected from the groupconsisting of nitrogen, oxygen and sulphur,

that ring being optionally substituted by halo, C₁-C₈-alkyl optionallysubstituted by —NR⁶R⁷, carboxy, C₁-C₈-alkoxycarbonyl or a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur,C₁-C₈-alkoxy, —NR⁶R⁷, C₃-C₈-cycloalkyl optionally substituted bycarboxy, or a 5 or 6-membered heterocyclic ring containing at least onehetero atom selected from the group consisting of nitrogen and oxygen,that ring being optionally substituted by C₁-C₈-alkyl;R² is C₁-C₈-alkyl;R³ is C₁-C₈-alkoxy, C₁-C₈-alkylcarbonyl, —SO₂NR⁸R⁹, —SOR¹⁰, —SO₂R¹¹ orcarboxy and is in the para or meta position with respect to theindicated thiazole ring;R⁴ is hydrogen, C₁-C₈-alkoxy optionally substituted by a 5 or 6-memberedheterocyclic ring containing at least one hetero atom selected from thegroup consisting of nitrogen, oxygen and sulphur, halo,halo-C₁-C₈-alkyl, —SO₂NH₂, —NR¹²R¹³ or a 5 or 6-membered heterocyclicring containing at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulphur, that ring being optionallysubstituted by C₁-C₈-alkyl;R⁵ is hydrogen;R⁶ is hydrogen or C₁-C₈-alkyl;R⁷ is C₁-C₈-alkyl optionally substituted by hydroxy,di(C₁-C₈-alkyl)amino or a 5 or 6-membered heterocyclic ring containingat least one hetero atom selected from the group consisting of nitrogenand oxygen, that ring being optionally substituted by C₁-C₈-alkyl;R⁸ is hydrogen or C₁-C₈-alkyl optionally substituted bydi(C₁-C₈-alkyl)amino;R⁹ is hydrogen, C₁-C₈-alkyl optionally substituted by hydroxy, orC₃-C₈-cycloalkyl;R¹⁰ is C₁-C₈-alkyl;R¹¹ is C₁-C₈-alkyl;R¹² is C₁-C₈-alkyl; andR¹³ is C₁-C₈-alkyl optionally substituted by di(C₁-C₈-alkyl)amino.

Further preferred compounds of formula I include those, in free or saltform, wherein R¹ is a 5 or 6-membered heterocyclic ring containingnitrogen and optionally one or more further hetero atoms selected fromthe group consisting of nitrogen, oxygen and sulphur,

that ring being optionally substituted by halo, C₁-C₄-alkyl optionallysubstituted by —NR⁶R⁷, carboxy, C₁-C₄-alkoxycarbonyl or a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur,C₁-C₄-alkoxy, —NR⁶R⁷, C₃-C₆-cycloalkyl optionally substituted bycarboxy, or a 5 or 6-membered heterocyclic ring containing at least onehetero atom selected from the group consisting of nitrogen and oxygen,that ring being optionally substituted by C₁-C₄-alkyl;R² is C₁-C₄-alkyl;R³ is C₁-C₄-alkoxy, C₁-C₄-alkylcarbonyl, —SO₂NR⁸R⁹, —SOR¹⁰, —SO₂R¹¹ orcarboxy and is in the para or meta position with respect to theindicated thiazole ring;R⁴ is hydrogen, C₁-C₄-alkoxy optionally substituted by a 5 or 6-memberedheterocyclic ring containing at least one hetero atom selected from thegroup consisting of nitrogen, oxygen and sulphur, halo,halo-C₁-C₄-alkyl, —SO₂NH₂, —NR¹²R¹³ or a 5 or 6-membered heterocyclicring containing at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulphur, that ring being optionallysubstituted by C₁-C₄-alkyl;R⁵ is hydrogen;R⁶ is hydrogen or C₁-C₄-alkyl;R⁷ is C₁-C₄-alkyl optionally substituted by hydroxy,di(C₁-C₄-alkyl)amino or a 5 or 6-membered heterocyclic ring containingat least one hetero atom selected from the group consisting of nitrogenand oxygen, that ring being optionally substituted by C₁-C₄-alkyl;R⁸ is hydrogen or C₁-C₄-alkyl optionally substituted bydi(C₁-C₄-alkyl)amino;R⁹ is hydrogen, C₁-C₄-alkyl optionally substituted by hydroxy, orC₃-C₅-cycloalkyl;R¹⁰ is C₁-C₄-alkyl;R¹¹ is C₁-C₄-alkyl;R¹² is C₁-C₄-alkyl; andR¹³ is C₁-C₄-alkyl optionally substituted by di(C₁-C₄-alkyl)amino.

Many of the compounds represented by formula I are capable of formingacid addition salts, particularly pharmaceutically acceptable acidaddition salts. Pharmaceutically acceptable acid addition salts of thecompound of formula I include those of inorganic acids, for example,hydrohalic acids such as hydrofluoric acid, hydrochloric acid,hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid,phosphoric acid; and organic acids, for example aliphatic monocarboxylicacids such as formic acid, acetic acid, trifluoroacetic acid, propionicacid and butyric acid, aliphatic hydroxy acids such as lactic acid,citric acid, tartaric acid or malic acid, dicarboxylic acids such asmaleic acid or succinic acid, aromatic carboxylic acids such as benzoicacid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid,aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoicacid, 1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. These salts may beprepared from compounds of formula I by known salt-forming procedures.

Compounds of formula I which contain acidic, e.g. carboxyl, groups, arealso capable of forming salts with bases, in particular pharmaceuticallyacceptable bases such as those well known in the art; suitable suchsalts include metal salts, particularly alkali metal or alkaline earthmetal salts such as sodium, potassium, magnesium or calcium salts, orsalts with ammonia or pharmaceutically acceptable organic amines orheterocyclic bases such as ethanolamines, benzylamines or pyridine.These salts may be prepared from compounds of formula I by knownsalt-forming procedures.

In those compounds where there is an asymmetric carbon atom thecompounds exist in individual optically active isomeric forms or asmixtures thereof, e.g. as racemic or diastereomeric mixtures. Thepresent invention embraces both individual optically active R and Sisomers as well as mixtures, e.g. racemic or diastereomeric mixtures,thereof.

Specific preferred compounds of formula I are described hereinafter inthe Examples.

The invention provides, in another aspect, a process for preparing acompound of formula I in free or salt form which comprises the steps of:

(i) (A) reacting a compound of formula II

-   -   wherein R², R³, R⁴ and R⁵ are as hereinbefore defined and X is        halogen, with a compound of formula III

-   -   wherein R¹ is as hereinbefore defined;    -   (B) reacting a compound of formula IV

-   -   wherein R², R³, R⁴ and R⁵ are as hereinbefore defined and X is        halogen, with a compound of formula R¹—NH², optionally in the        presence of a base;    -   (C) for the preparation of compounds of formula I where R¹ is a        5 or 6-membered heterocyclic ring containing nitrogen and        optionally a further hetero atom of the group consisting of        nitrogen, oxygen and sulphur that is substituted by —NR⁶R⁷,        reacting a compound of formula I where R¹ is a 5 or 6-membered        heterocyclic ring containing nitrogen and optionally a further        hetero atom of the group consisting of nitrogen, oxygen and        sulphur that is substituted by halo with a compound of formula V

-   -   wherein R⁶ and R⁷ are as hereinbefore defined, optionally in the        presence of a base;    -   (D) for the preparation of compounds of formula I where R³ is        —SO₂NR⁸R⁹, reacting a compound of formula VI

-   -   wherein R², R⁴, R⁵ and X are as hereinbefore defined with an        amine of formula VII

-   -   wherein R⁸ and R⁹ are as hereinbefore defined;    -   (E) for the preparation of compounds of formula I where one or        both of R⁴ and R⁵ is —NR¹²R¹³, reacting a compound of formula I        wherein R¹ and R² are hereinbefore defined, R³ is —SO₂R¹¹ or        —SO₂NH₂ and one or both of R⁴ and R⁵ is halo with a compound of        formula VIII

-   -   wherein R¹² and R¹³ are hereinbefore defined, optionally in the        presence of a base; or    -   (F) for the preparation of compounds of formula I where one or        both of R⁴ and R⁵ is C₁-C₈-alkoxy substituted by a 5 or        6-membered heterocyclic ring containing at least one hetero atom        selected from the group consisting of nitrogen, oxygen and        sulphur, reacting a compound of formula I wherein R¹ and R² are        hereinbefore defined, R³ is —SO₂R¹¹ or —SO₂NH₂ and one or both        of R⁴ and R⁵ is halo with a compound of formula HO—C₁-C₈-alkyl-W        where W is a 5 or 6-membered heterocyclic ring containing at        least one hetero atom selected from the group consisting of        nitrogen, oxygen and sulphur, optionally in the presence of a        base; and        (ii) recovering the resultant compound of formula I in free or        salt form.

Process variant (A) may be carried out using known procedures forpreparing aminothiazoles, or analogously, e.g. as hereinafter describedin the Examples. The halogen X is preferably bromine or iodine. Thereaction may be carried out in an organic solvent, e.g. an alcohol, suchas ethanol, or pyridine. When the halogen is iodine and the solvent ispyridine the compounds of formula II are formed in situ. The reactiontemperature may be from room temperature to the reflux temperature ofthe solvent, but conveniently from about 40 to 60° C. to the refluxtemperature of the solvent.

Process variant (B) may be carried out using known procedures forreaction of hetero aryl halides with primary or secondary amines, oranalogously, e.g. as hereinafter described in the Examples. The halogenX is preferably chlorine or bromine. The reaction may be carried out inan organic solvent, e.g. dimethylacetamide or dimethylsulfoxide, andwhen it is carried out in the presence of an alkali metal salt thatalkali metal salt is preferably caesium carbonate. The reactiontemperature may be from room temperature to the reflux temperature ofthe solvent, but conveniently about 110 to 130° C.

Process variant (C) may be carried out using known procedures forreaction of heteroaryl halides with primary or secondary amines, oranalogously, e.g. as hereinafter described in the Examples. It may becarried out neat but when it is carried out in the presence of an alkalimetal salt that salt is preferably caesium carbonate. The reactiontemperature may be from 50 to 200° C., but conveniently about 90 to 110°C.

Process variant (D) may be carried out using known procedures forreacting sulfonyl chlorides with amines, or analogously, e.g. ashereinafter described in the Examples. The reaction may be carried outin an organic solvent, e.g. dioxane. The reaction temperature may befrom room temperature to the reflux temperature of the solvent, butconveniently room temperature.

Process variant (E) may be carried out using known procedures forreacting aryl halides with amines. The reaction may be carried out in anorganic solvent, for example dimethylformamide (DMF) but preferablydimethylsulfoxide (DMSO), preferably in the presence of a base, which ispreferably caesium carbonate. The reaction temperature is conveniently100 to 150° C.

Process variant (F) may be carried out using known procedures forreacting aryl halides with alcohols. The reaction may be carried out inan organic solvent, for example dimethylformamide (DMF) but preferablydimethylsulfoxide (DMSO), preferably in the presence of a base, which ispreferably caesium carbonate. The reaction temperature is conveniently100 to 150° C.

Compounds of formula II may be prepared by reacting a compound offormula IX

wherein R², R³, R⁴ and R⁵ are as hereinbefore defined, with a halogen,preferably bromine or iodine, using known procedures for the alphahalogenation of ketones.

Compounds of formula III may be prepared by known methods, for exampleby reacting a compound of formula R¹—NH₂, where R¹ is as hereinbeforedefined, with benzoyl isothiocyanate and hydrolysing the resultingproduct, for example to replace the benzoyl group by hydrogen, e.g. ashereinafter described in the Examples. The reaction with benzoylisothiocyanate may be carried out in an organic solvent, for example analcohol such as ethanol. Suitable reaction temperatures are from roomtemperature to reflux temperature of the solvent, conveniently 35-45° C.The hydrolysis may be effected at elevated temperature, for example 60to 80° C. to reflux temperature, conveniently at reflux temperature.

Compounds of formula IV may be prepared from aminothiazole compounds byknown reactions for conversion of aryl or heteroaryl amines to aryl orheteroaryl halides, for example by diazotization of the heteroaryl aminefollowed by addition of the diazonium salt to the copper(II) halide inan aqueous solution with the corresponding halogeno acid (SandmeyerReaction) or by treatment of the heteroaryl amine with an alkyl nitritein the presence of anhydrous copper (U) salts as described in M. P.Doyle, B. Siegfried, J. F. Dellaria, Jr., Journal of Organic Chemistry,42, 1977, p 2426. Compounds of formula V are either commerciallyavailable or may be prepared by known methods.

Compounds of formula VI may be prepared from compounds of formula Iwherein R³ is nitro by known reactions for converting arylnitro-substituted compounds to their corresponding aryl sulfonylchlorides, for example by firstly hydrogenating to the aniline, e.g.using hydrogen in the presence of 10% Palladium on carbon, then secondlyreacting with nitrous acid to give the diazo compound and finallyreacting with SO₂/acetic acid/CuCl₂H₂O. The first step may be carriedout in an organic solvent, for example a mixture of ethyl acetate andtetrahydrofuran. Suitable reaction temperatures are from roomtemperature to reflux temperature of the solvent, but conveniently roomtemperature.

Compounds of formula VII are either commercially available or may beprepared by known methods.

Compounds of formula VIII are either commercially available or may beprepared by known methods.

Compounds of formula IX where R³ is —SO₂NR⁸R⁹ may be prepared asdescribed in EP 91749 A2.

Compounds of formula IX where R³ is —SO₂NR⁸R⁹ may be prepared byreacting a compound of formula IX where R³ is hydrogen and R⁴ is—C₁-C₈-alkoxy or chlorine, with chlorosulfonic acid, followed bytreatment with an amine or ammonia as described in the Examples.

Compounds of formula IX where R³ is —SO₂NR⁸R⁹ may also be prepared fromthe compound of formula IX where R³ is —NH₂, R⁴ and R⁵ being hydrogen,by reaction with nitrous acid to give a diazo compound which is thenreacted with sulphur dioxide in the presence of copper chloride, forexample by the method described in E. E. Gilbert, Synthesis 1969, 1-10,to give the corresponding sulfonyl chloride of formula IX where R³ ismeta SO₂Cl, R⁴ and R⁵ being hydrogen. This is then treated with ammoniaor an amine as described in the Examples.

Compounds of formula IX where R³ is —NH₂, R² is methyl and R⁴ and R⁵ arehydrogen, may be prepared from the compound of formula IX where R³ is—NO₂, R⁴ and R⁵ being hydrogen, by hydrogenation, e.g. using hydrogen inthe presence of 10% palladium on carbon, in an organic solvent, forexample a mixture of ethyl acetate and tetrahydrofuran (THF).

Compounds of formula IX where R³ is —SO₂R¹¹, R⁴ is -fluoride or-trifluoromethyl and R⁵ is hydrogen may be prepared from compounds offormula X where R⁴ is F or CF₃ by known methods, for example asdescribed in R. V. Heinzelman, Org. Synth., 1963, IV, 573.

The compound of formula X where R⁴ is chlorine may be prepared asdescribed in international patent application WO 01/49660 A1.

Compounds of formula X where R⁴ is fluorine or trifluoromethyl may beprepared from commercially available compounds of formula XI where R⁴ isfluorine or trifluoromethyl by reaction with the sodium salt of methanesulfinic acid in an organic solvent, for example dimethylsulfoxide(DMSO). The reaction temperature may be from room temperature to 100° C.but conveniently about 70° C.

Compounds of formula XI are either commercially available or may beprepared by known methods.

Compounds of formula I and their pharmaceutically acceptable salts areuseful as pharmaceuticals. In particular, they exhibit inhibition ofphosphatidylinositol 3-kinase (Pi3 kinase) enzymes, especially the gammaisoform (p110γ), which are responsible for generating phosphorylatedsignalling products. The inhibitory properties of compounds of formula Imay be demonstrated in the following test procedures:

Baculovirus expressing different fragments of human PI3Kγ fused toglutathione S-transferase (GST) have been previously described byStoyanova, S., Bulgarelli-Leva, G., Kirsch, C., Hanck, T., Klinger, R.,Wetzker, R., Wymann, M. P. (1997) Lipid- and protein kinase activitiesof G protein-coupled PI 3-kinase g: structure-activity analysis andinteractions with wortmannin. Biochem. J., 324:489. Residues 38-1102 ofhuman PI3Kγ are subcloned into the BamH1 and EcoR1 sites of the transfervector pAcG2T (Pharmingen) to create a GST-PI3Kγ lacking the first 37residues of PI3Kγ. To express the recombinant protein, Sf9 (Spodopterafrugiperda 9) insect cells are routinely maintained at densities between3×10⁵ and 3×10⁶ cells/ml in serum containing TNMPH medium (Sigma). Sf9cells, at a density of 2×10⁶ are infected with human GST-PI3KγΔ34baculovirus at a multiplicity of infection (m.o.i.) of 1 for 72 hours.The infected cells are harvested by centrifugation at 1400 g for 4minutes at 4° C. and the cell pellets are frozen at −80° C. Both Sf9 andSf21 cells work equally well. Sf9 cells (1×10⁹) are resuspended in 100ml cold (4° C.) lysis buffer (50 mM Tris-HCl pH 7.5, 1% Triton X-100,150 mM NaCl, 1 mM NaF, 2 mM DTT and protease inhibitors. Cells areincubated on ice for 30 minutes then centrifuged at 15000 g for 20minutes at 4° C. Purification of the supernatant sample is carried outat 4° C. by affinity chromatography using SEPHAROSE™ agarose gel beadscoupled to glutathione (from Amersham Pharmacia Biotech). A celllysate/GST resin ratio of 50:1 is used. The GST resin is firstlypre-rinsed to remove ethanol preservative and then equilibrated withlysis buffer. Cell lysate (supernatant) is added (usually as 50 mllysate to 1 ml GST resin in 50 ml tubes) and gently rotated on a mixerat 4° C. for 2-3 hours. The unbound flow through sample is collected bycentrifugation at 1000 g for 5 minutes at 4° C. using a DENLEY™centrifuge. The 1 ml GST resin containing bound material is transferredto a 15 ml FALCON™ centrifuge tube for subsequent washing and elutionsteps. Firstly a series of 3 cycles of washings (mixing by gentleinversion) is performed with 15 ml ice cold wash Buffer A (50 mMTris-HCl pH 7.5, 1% Triton X-100, 2 mM DTT) interspersed withcentrifugation at 1000 g for 5 minutes at 4° C. A final single wash stepis performed with 15 ml ice cold wash Buffer B (50 mM Tris-HCl pH 7.5, 2mM DTT) and then centrifuged at 1000 g for 5 minutes at 4° C. The washedGST resin is finally eluted with 4 cycles of 1 ml ice cold elutionbuffer (50 mM Tris-HCl pH 7.5, 10 mM reduced glutathione, 2 mM DTT, 150mM NaCl, 1 mM NaF, 50% ethylene glycol and protease inhibitors)interspersed with centrifugation at 1000 g for 5 minutes at 4° C.Samples are aliquoted and stored at −20° C.

An in vitro kinase assay was established that measures the transfer ofthe terminal phosphate of adenosine triphosphate tophosphatidylinositol. The kinase reaction is performed in a white 96well microtitre plate as a Scintillation Proximity Assay. Each wellcontains 10 μl test compound in 5% dimethylsulphoxide and 20 μl assaymix (40 mM Tris, 200 mM NaCl, 2 mM ethyleneglycol-aminoethyl-tetraaceticacid (EGTA), 15 μg/ml phosphatidylinositol, 12.5 μM adenosinetriphosphate (ATP), 25 mM MgCl₂, 0.1 μCi [³³P]ATP). The reaction isstarted by the addition of 20 μl of enzyme mix (40 mM Tris, 200 mM NaCl,2 mM EGTA containing recombinant GST-p110γ). The plate is incubated atroom temperature for 60 minutes and the reaction terminated by theadding 150 μl of WGA-bead stop solution (40 mM Tris, 200 mM NaCl, 2 mMEGTA, 1.3 mM ethylene diamine tetraacetic acid (EDTA), 2.6 μM ATP and0.5 mg of Wheat Germ Agglutinin-SPA beads (Amersham Biosciences) to eachwell. The plate is sealed, incubated at room temperature for 60 minutes,centrifuged at 1200 rpm and then counted for 1 minute using ascintillation counter. Total activity is determined by adding 10 μl of5% dimethylsulphoxide (DMSO) and non-specific activity is determined byadding 10 μl 50 mM EDTA in place of the test compound.

Compounds of the Examples hereinbelow have IC₅₀ values below 0.60 μM inthe aforementioned assay.

Having regard to their inhibition of phosphatidylinositol 3-kinaseenzymes, compounds of formula I in free or pharmaceutically acceptablesalt form, hereinafter alternately referred to as “agents of theinvention”, are useful in the treatment of conditions which are mediatedby the activation of the Pi3 kinase enzymes, particularly inflammatoryor allergic conditions. Treatment in accordance with the invention maybe symptomatic or prophylactic.

Accordingly, agents of the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodelling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.(For convenience this particular asthmatic condition is referred to as“wheezy-infant syndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e. therapy for or intendedto restrict or abort symptomatic attack when it occurs, for exampleanti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylacticbenefit in asthma may in particular be apparent in subjects prone to“morning dipping”. “Morning dipping” is a recognised asthmatic syndrome,common to a substantial percentage of asthmatics and characterised byasthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions towhich the present invention is applicable include acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy. The invention isalso applicable to the treatment of bronchitis of whatever type orgenesis including, e.g., acute, arachidic, catarrhal, croupus, chronicor phthinoid bronchitis. Further inflammatory or obstructive airwaysdiseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siaerosis, silicosis, tabacosis and byssinosis.

Having regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, agents of the inventionare also useful in the treatment of eosinophil related disorders, e.g.eosinophilia, in particular eosinophil related disorders of the airways(e.g. involving morbid eosinophilic infiltration of pulmonary tissues)including hypereosinophilia as it effects the airways and/or lungs aswell as, for example, eosinophil-related disorders of the airwaysconsequential or concomitant to Löffler's syndrome, eosinophilicpneumonia, parasitic (in particular metazoan) infestation (includingtropical eosinophilia), bronchopulmonary aspergillosis, polyarteritisnodosa (including Churg-Strauss syndrome), eosinophilic granuloma andeosinophil-related disorders affecting the airways occasioned bydrug-reaction.

Agents of the invention are also useful in the treatment of inflammatoryor allergic conditions of the skin, for example psoriasis, contactdermatitis, atopic dermatitis, alopecia greata, erythema multiforma,dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivityangiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus,epidermolysis bullosa acquisita, and other inflammatory or allergicconditions of the skin.

Agents of the invention may also be used for the treatment of otherdiseases or conditions, in particular diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as conjunctivitis, keratoconjunctivitissicca, and vernal conjunctivitis, diseases affecting the nose includingallergic rhinitis, and inflammatory disease in which autoimmunereactions are implicated or having an autoimmune component or aetiology,including autoimmune haematological disorders (e.g. haemolytic anaemia,aplastic anaemia, pure red cell anaemia and idiopathicthrombocytopenia), systemic lupus erythematosus, polychondritis,sclerodoma, Wegener granulamatosis, dermatomyositis, chronic activehepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue,autoimmune inflammatory bowel disease (e.g. ulcerative colitis andCrohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary billiary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy).

Other diseases or conditions which may be treated with agents of theinvention include septic shock, rheumatoid arthritis, osteoarthritis,proliferative diseases such as cancer, atherosclerosis, allograftrejection following transplantation, stroke, obesity, restenosis,diabetes, e.g. diabetes mellitus type I (juvenile diabetes) and diabetesmellitus type II, diarrheal diseases, ischemia/reperfusion injuries,retinopathy, such as diabetic retinopathy or hyperbaric oxygen-inducedretinopathy, and conditions characterised by elevated intraocularpressure or secretion of ocular aqueous humor, such as glaucoma.

The effectiveness of an agent of the invention in inhibitinginflammatory conditions, for example in inflammatory airways diseases,may be demonstrated in an animal model, e.g. a mouse or rat model, ofairways inflammation or other inflammatory conditions, for example asdescribed by Szarka et al, J. Immunol. Methods (1997) 202:49-57; Renziet al, Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J.Clin. Invest. (1995) 96:2924-2931; and Cernadas et al (1999) Am. J.Respir. Cell Mol. Biol. 20:1-8.

The agents of the invention are also useful as co-therapeutic agents foruse in combination with other drug substances such as anti-inflammatory,bronchodilatory or antihistamine drug substances, particularly in thetreatment of obstructive or inflammatory airways diseases such as thosementioned hereinbefore, for example as potentiators of therapeuticactivity of such drugs or as a means of reducing required dosaging orpotential side effects of such drugs. An agent of the invention may bemixed with the other drug substance in a fixed pharmaceuticalcomposition or it may be administered separately, before, simultaneouslywith or after the other drug substance. Accordingly the inventionincludes a combination of an agent of the invention as hereinbeforedescribed with an anti-inflammatory, bronchodilatory or antihistaminedrug substance, said agent of the invention and said drug substancebeing in the same or different pharmaceutical composition. Suchanti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate and compoundsdescribed in WO 0200679, WO 0288167, WO 0212266 and WO 02100879, LTB4antagonists such as those described in U.S. Pat. No. 5,451,700, LTD4antagonists such as montelukast and zafirlukast, dopamine receptoragonists such as cabergoline, bromocriptine, ropinirole and4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)-propyl]-sulfonyl]ethyl]-amino]ethyl]-2(3H)-benzothiazoloneand pharmaceutically acceptable salts thereof (the hydrochloride beingViozan®—AstraZeneca), and PDE4 inhibitors such as Ariflo®(GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004(Bayer), SCH-351591 (Schering-Plough), Arofylline (AlmirallProdesfarma), PD189659 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801(Celgene) and KW-4490 (Kyowa Hakko Kogyo) as well as those described inWO 98/18796 and WO 03/39544. Such bronchodilatory drugs includeanticholinergic or antimuscarinic agents, in particular ipratropiumbromide, oxitropium bromide and tiotropium salts but also thosedescribed in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO03/87094, WO 04/05285, WO 02/00652, WO 03153966, EP 424021, U.S. Pat.No. 5,171,744, U.S. Pat. No. 3,714,357 and WO 03/33495, and beta-2adrenoceptor agonists such as salbutamol, terbutaline, salmeterol and,especially, formoterol and pharmaceutically acceptable salts thereof,and compounds (in free or salt or solvate form) of formula I of PCTInternational patent publication No. WO 00/75114, which document isincorporated herein by reference, preferably compounds of the Examplesthereof, especially a compound of formula

and pharmaceutically acceptable salts thereof. Co-therapeuticantihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride.Combinations of agents of the invention and steroids, beta-2 agonists,PDE4 inhibitors or LTD4 antagonists may be used, for example, in thetreatment of COPD or, particularly, asthma. Combinations of agents ofthe invention and anticholinergic or antimuscarinic agents, PDE4inhibitors, dopamine receptor agonists or LTB4 antagonists may be used,for example, in the treatment of asthma or, particularly, COPD.

Other useful combinations of agents of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO00/66558 (particularlyclaim 8), and WO00/66559 (particularly claim 9).

The agents of the invention may be administered by any appropriateroute, e.g. orally, for example in the form of a tablet or capsule;parenterally, for example intravenously; by inhalation, for example inthe treatment of inflammatory or obstructive airways disease;intranasally, for example in the treatment of allergic rhinitis;topically to the skin, for example in the treatment of atopicdermatitis; or rectally, for example in the treatment of inflammatorybowel disease.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula I in free form or in the form of apharmaceutically acceptable salt, optionally together with apharmaceutically acceptable diluent or carrier therefor. The compositionmay contain a co-therapeutic agent such as an anti-inflammatory,bronchodilatory or antihistamine drug as hereinbefore described. Suchcompositions may be prepared using conventional diluents or excipientsand techniques known in the galenic art. Thus oral dosage forms mayinclude tablets and capsules.

Formulations for topical administration may take the form of creams,ointments, gels or transdermal delivery systems, e.g. patches.Compositions for inhalation may comprise aerosol or other atomizableformulations or dry powder formulations.

When the composition comprises an aerosol formulation, it preferablycontains, for example, a hydro-fluoro-alkane (HFA) propellant such asHFA134a or HFA227 or a mixture of these, and may contain one or moreco-solvents known in the art such as ethanol (up to 20% by weight),and/or one or more surfactants such as oleic acid or sorbitan trioleate,and/or one or more bulking agents such as lactose. When the compositioncomprises a dry powder formulation, it preferably contains, for example,the compound of formula I having a particle diameter up to 10 microns,optionally together with a diluent or carrier, such as lactose, of thedesired particle size distribution and a compound that helps to protectagainst product performance deterioration due to moisture. When thecomposition comprises a nebulised formulation, it preferably contains,for example, the compound of formula I either dissolved, or suspended,in a vehicle containing water, a co-solvent such as ethanol or propyleneglycol and a stabiliser, which may be a surfactant.

Dosages of agents of the invention employed in practicing the presentinvention will of course vary depending, for example, on the particularcondition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for oraladministration are of the order of 0.1 to 10 mg/kg.

EXAMPLES

Compounds of formula I which are also of formula XII

are shown in Table I below, the method of preparation being describedhereinafter. The table also shows mass spectrometry data. The Examplesare in free form.

TABLE 1 M/s Ex. R^(a) R^(b) R¹ MH+  1 —SO₂NH₂ H

347.9  2 —SO₂NH₂ H

381.9  3 —SO₂NH₂ H

378.1  4 —SO₂NH₂ H

347.0  5 —SO₂NH₂ H

381.1  6 —SO₂NH₂ H

390.9  7 —SO₂NH₂ H

347.0  8 —SO₂NH₂ H

376.9  9 —SO₂NH₂ H

347.0 10 —SO₂NH₂ H

348.1 11 —SO₂NH₂ H

378.0 12 —SO₂NH₂ H

382.0 13 —SO₂NH₂ H

446.2 14 —SO₂NH₂ H

433.2 15 —SO₂NH₂ H

475.9 16 —SO₂NH₂ H

421.2 17 —SO₂NH₂ H

476.0 18

H

392.2 19

H

362.2 20

H

418.2 21

H

388.2 22 —OCH₃ —SO₂NH₂

378.2 23 —SO₂NH₂ Cl

381.9 24 —SO₂NH₂ Cl

380.9 25 —SO₂NH₂ H

367.9 26 —SO₂NH₂ H

336.9 27

H

330.9 28

H

 346.99 29

H

380.8 30

Cl

 379.99 31

H

443.8

Preparation of Specific Examples Example 14-[4-Methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide 1a)Pyrazin-2-yl-thiourea

Aminopyrazine (2 g, 21.03 mmol) is dissolved in ethanol (20 ml) andbenzoylisothiocyanate (2.82 ml) is added dropwise. The mixture is heatedto 80° C. with stirring for 10 minutes then allowed to cool to roomtemperature. The solvent is removed in vacuo and the resulting soliddissolved in 1M sodium hydroxide (30 ml) and heated under reflux for 1hour. The resultant suspension is filtered and the solid washed withwater and a little cold methanol. The solid is dried in vacuo to yieldthe title compound, m.p. 239-239.5° C., MH⁺ (AP+): 138 (M⁺-NH₃).

Other thioureas used are either commercially available or prepared in ananalogous manner from the appropriate starting amine.

1b) 4-[4-Methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

Bromine (0.017 ml, 0.33 mmol) is added dropwise to a stirred solution of4-(2-oxo-propyl)-benzenesulfonamide (prepared as described in Europeanpatent specification EP 91749 A2) (0.087 g, 4.1 mmol) in dioxan (10 ml)at 0° C. After 30 minutes the solvent is removed and the crude productis dissolved in ethanol (4.0 ml). Pyrazin-2-yl-thiourea (0.063 g, 0.41mmol) is added and the stirred reaction mixture is heated at 60° C. for3 hours. The solvent is removed and the residue is triturated with ethylacetate to give the title compound as a pale orange solid (0.040 g). MH⁺(AP+):

Example 24-[2-(6-Chloro-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide

4-(2-Oxo-propyl)-benzenesulfonamide (prepared as described in Europeanpatent specification EP 91749 A2) (0.63 g, 2.9 mmol) is dissolved in drydioxan (70 ml) at 0° C. and bromine (0.121 ml, 2.4 mmol) is addeddropwise. The mixture is stirred for 45 minutes at room temperature thenthe solvent is removed in vacuo. 6-Chloro-pyrazin-2-yl-thiourea (0.35 g,1.87 mmol) is added to a solution of the above bromide (0.546 g, 1.87mmol) in ethanol and the solution is heated at 60° C. for 4 hours. Thereaction mixture is allowed to cool and the solvent removed under vacuumto give the title compound (0.63 g). MH⁺ (ES+): 382.1, 384.2 (3:1)

Examples 3 to 12

These compounds, namely

-   4-[2-(6-methoxy-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide,-   4-[4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,-   4-[2-(5-chloro-pyridin-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide,-   4-[2-(6-ethoxy-pyridin-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide,-   4-[4-methyl-2-(pyridin-3-ylamino)-thiazol-5-yl]-benzenesulfonamide,-   4-[2-(6-methoxy-pyridin-3-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide,-   4-[4-methyl-2-(pyridin-4-ylamino)-thiazol-5-yl]-benzenesulfonamide,-   4-[4-methyl-2-(pyrimidin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,-   4-[2-(6-methoxy-pyrimidin-4-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide    and-   4-[2-(6-chloro-pyridazin-3-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide    respectively, are prepared by the procedure of Example 2 from    4-(2-oxo-propyl)-benzenesulfonamide (prepared as described in    European patent specification EP 91749 A2) and the appropriate    thiourea.

Example 134-[4-Methyl-2-(4-methyl-3,4,5,6-tetrahydro-2.H.-[1,2]bipyrazinyl-6′-ylamino)-thiazol-5-yl]-benzenesulfonamide

4-[2-(6-Chloro-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide(2) (50 mg, 0.13 mmol) and 1-methylpiperazine (0.147 ml, 1.31 mmol) areheated, with stirring under argon, at 80° C. for 18 hours. The reactionmixture is azeotroped with toluene (2×20 ml) then dissolved in ethylacetate and washed with water (50 ml) followed by brine (50 ml). Afterdrying (MgSO₄) the mixture is filtered and the solvent is removed togive a brown solid. Addition of CH₂Cl₂ affords the title compound (0.013g).

Examples 14 to 17

These compounds, namely4-[4-methyl-2-(6-morpholin-4-yl-pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,4-{4-methyl-2-[6-(2-morpholin-4-yl-ethylamino)-pyrazin-2-ylamino]-thiazol-5-yl}-benzenesulfonamide,4-{2-[6-(3-hydroxy-propylamino)-pyrazin-2-ylamino]-4-methyl-thiazol-2-yl}-benzenesulfonamideand4-{2[6-(3-diethylamino-propylamino)-pyrazin-2-ylamino]-4-methyl-thiazol-5-yl}-benzenesulfonamiderespectively, are prepared from4-[2-(6-chloro-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamide(Example 2) and the appropriate amine following the procedure of Example11.

Example 184-[2-(6-Methoxy-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-N-methyl-benzene-sulfonamide18a) N-Methyl-4-(2-oxo-propyl)-benzenesulfonamide

4-(2-Oxo-propyl)-benzenesulfonyl chloride (prepared as described inEuropean patent specification EP 91749 A2) (0.087 g, 4.1 mmol) wastreated with methylamine to give the title compound.

18b)4-[2-(6-Methoxy-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-N-methyl-benzene-sulfonamide

Using N-methyl-4-(2-oxo-propyl)-benzenesulfonamide (18a) and(6-methoxy-pyrazin-2-yl)-thiourea in an identical process to thatdescribed for the preparation of4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide(Example 1) afforded the title compound.

Examples 19 to 21

These compounds, namelyN-methyl-4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,N-cyclopropyl-4-[2-(6-methoxy-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamideandN-cyclopropyl-4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamiderespectively, are prepared by analogous procedures to those used for4-[2-(6-methoxy-pyrazin-2-ylamino)-4-methyl-thiazol-5-yl]-N-methyl-benzenesulfonamide(Example 16), starting from 4-(2-oxo-propyl)-benzenesulfonyl chloride(prepared as described in European patent specification EP 91749 A2) andusing the appropriate amine and thiourea.

Example 222-Methoxy-5-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide (S. Sakurai et al. Chem.Pharm. Bull. 40(6) 1443-1451 (1992)) (0.3 g, 1.23 mmol),pyrazin-2-yl-thiourea (0.19 g, 1.23 mmol), iodine (0.31 g, 1.23 mmol) inpyridine (2.5 ml) is stirred at 60° C. for 20 hours. The mixture isconcentrated. To the residue is added water, the precipitate iscollected and recrystallised from ethanol to give the titled compound(0.103 g). m.p. 378.2° C.

Example 232-Chloro-4-[4-methyl-2-pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide23a) 1-(4-Amino-3-chloro-phenyl)-propan-2-one

N-Chlorosuccinamide (1.79 g, 13.4 mmol) is added to a stirred solutionof 1-(4-amino-phenyl)-propan-2-one (2.0 g, 13.4 mmol) in chloroform at0° C. After 1 hour the reaction is complete. The solvent is removed togive the title compound.

23b) 2-Chloro-4-(2-oxo-propyl)-benzenesulfonyl chloride

Concentrated hydrochloric acid (4 ml) is added slowly to a stirredsolution of 1-(4-Amino-3-chloro-phenyl)-propan-2-one (23a) (2.4 g, 13.1mmol) in acetic acid (80 ml) at 0° C. A solution of sodium nitrite (0.90g, 13.1 mmol) in water (4.0 ml) is added dropwise. After 20 minutes asolution of the above reagent (SO₂/AcOH/CuCl₂/H₂O) (100 ml) at 0° C. isadded and the mixture is allowed to warm to room temperature and stirredfor 1 hour. The mixture is diluted with water (100 ml) and extractedwith dichloromethane (3×100 ml). The organic extracts are combined,washed with brine (100 ml), dried (MgSO₄), filtered and the solvent isremoved to afford the title compound (3.5 g) which is used crude in thesubsequent reaction.

Preparation of the Reagent SO₂/AcOH/CuCl₂/H₂O:

In accordance with the method described in E. E. Gilbert, Synthesis1969, 1-10, p6, glacial acetic acid (100 ml) vigorously stirred at roomtemperature is treated by bubbling SO₂ gas. Once a saturated solution isachieved (approximately 10 g per 100 ml), the solution is treated withcopper (II) chloride (4 g) in water (5 ml). The resulting mixture isallowed to settle to give a green solution.

23c) 2-Chloro-4-(2-oxo-propyl)-benzenesulfonamide

Aqueous ammonia solution (5 ml) is added to a stirred solution of thecrude sulfonyl chloride (23b) (0.70 g, 2.62 mmol) in tetrahydrofuran(100 ml) at 0° C. After 2 hours the reaction mixture is concentrated invacuo. The residue is diluted with water (100 ml) and extracted withethyl acetate (100 ml). The organic extract is dried (MgSO₄) and thesolvent removed to give an oil. Purification by chromatography onsilica, eluting with ethyl acetate, affords the title compound (0.154g).

23d) 4-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide

Bromine 0.022 ml, 0.42 mmol) is added to a stirred solution of ketone(23c) (0.15 g, 6.1 mmol) in dioxan (15 ml). After 30 minutes the solventis removed to give a brown oil (0.2 g).

23e)2-Chloro-4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

Pyrazin-2-yl-thiourea (Example 1a) (0.047 g, 0.31 mmol) is added to astirred solution of 4-(1-bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide(0.10 g, 0.31 mmol) in ethanol (5 ml). The solution is heated at 60° C.for 3 hours. The mixture is filtered to remove the precipitate which iswashed with methanol and dried. (0.055 g).

Example 242-Chloro-4-[4-methyl-2-(pyridin-3-ylamino)-thiazol-5-yl]-benzenesulfonamide

3-Pyridylthiourea (0.047 g, 0.31 mmol) is added to a stirred solution of4-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (Example 23d) (0.10g, 0.31 mmol) in ethanol (5 ml). The solution is heated at 60° C. for 3hours. The solvent is removed and the residue is purified bychromatography on silica eluting with ethyl acetate-hexane to give thetitle compound (0.020 g).

Example 254-[4-Methyl-2-([1,3,4]thiadiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide25a) 4-Methyl-5-(4-nitro-phenyl)-thiazol-2-ylamine

A solution of N-[4-methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-acetamide(prepared by the method described in J. Liebscher, E. Mitzner,Synthesis, 1985, (4), p 414) (10 g, 36 mmol) in ethanol (200 ml) and 7Mhydrochloric acid (50 ml) is heated at reflux with stirring for 4 hours.After standing at room temperature for 4 days the hydrochloride salt ofthe title compound (8.15 g) precipitates as yellow crystals which areremoved by filtration and dried. The title compound (free base) isobtained by partitioning the hydrochloride salt between aqueous sodiumhydroxide and ethyl acetate. The organic extract is separated, dried(MgSO₄) and the solvent is removed to give an orange solid (6.58 g). 1Nnmr (CDCl₃): 2.38 (4H, s, Me), 5.02 (2H, br s, NH₂), 7.45 (2H, d), 8.20(2H, d)

25b) 2-Chloro-4-methyl-5-(4-nitro-phenyl)-thiazole

Isoamyl nitrite (3.5 ml, 25 mmol) is added to a stirredsuspension/solution of anhydrous copper (II) chloride (2.75 g, 20 mmol)in dry methylcyanide (50 ml).4-Methyl-5-(4-nitro-phenyl)-thiazol-2-ylamine (25a) (4.0 g, 17 mmol) isthen added over 30 minutes. The resulting slurry is stirred at roomtemperature for 1 hour then heated at 70° C. for 30 minutes. Aftercooling to room temperature the black solution is poured into 4Mhydrochloric acid (200 ml). The product is extracted with ethyl acetate,dried (MgSO₄) and the solvent removed to give the title compound as anorange powder (3.13 g). MH⁺ (TOF, ES+): 255.0

25c) 4-(2-Chloro-4-methyl-thiazol-5-yl)-phenylamine

Indium powder (0.64 mg, 2.5 mmol) and saturated ammonium chloridesolution (3 ml, 2.5 mmol) are added to a solution of2-chloro-4-methyl-5-(4-nitro-phenyl)-thiazole (25b) (0.20 g, 0.786 mmol)in ethanol (3 ml). The mixture is heated at reflux with stirring for 90minutes. When cool the mixture is diluted with 2M aqueous hydrochloricacid to dissolve any product and the mixture is filtered through celite.The filtrate is adjusted to pH 9 with aqueous sodium hydroxide andextracted with dichloromethane (3×30 ml). The combined organic extractis dried (MgSO₄) filtered, and the solvent removed to give the titlecompound as a yellow solid (0.17 g).

25d) 4-(2-Chloro-4-methyl-thiazol-5-yl)-benzenesulfonamide

Starting from 4-(2-chloro-4-methyl-thiazol-5-yl)-phenylamine (25c) andfollowing the two step process described for the preparation of2-chloro-4-(2-oxo-propyl)-benzenesulfonamide (Example 23c) from1-(4-amino-3-chloro-phenyl)-propan-2-one (Example 23a) gave the titlecompound.

25e)4-[4-Methyl-2-([1,3,4]thiadiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

Caesium carbonate (0.08 g, 0.24 mmol) and5-methyl-[1,3,4]thiadiazol-2-ylamine (0.031 g, 0.27 mmol) are added to asolution of 4-(2-chloro-4-methyl-thiazol-5-yl)-benzenesulfonamide (25d)(0.07 g, 0.24 mmol) in dimethylacetamide (2 ml). The mixture is heatedwith stirring at 110° C. for 18 hours. After adding more5-methyl-[1,3,4]thiadiazol-2-ylamine (0.056 g, 0.49 mmol) heating iscontinued at 130° C. for an additional 8 hours. The solvent is removedand the product is purified by chromatography on silica eluting withethyl acetate to give an orange solid. Trituration with ethylacetate-methanol affords the title compound as a yellow solid (0.0081 g)

Example 264-[4-Methyl-2-(1.H.-[1,2,4]triazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide

Replacing 5-methyl-[1,3,4]thiadiazol-2-ylamine with1.H.-[1,2,4]triazol-3-ylamine in the procedure described for preparing4-[4-methyl-2-([1,3,4]thiadiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide(Example 25e) from 4-(2-chloro-4-methyl-thiazol-5-yl)-benzenesulfonamide(Example 25d) affords the title compound.

Example 27[5-(4-Methanesulfinyl-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine27a) 1-Methylsulfanyl-4-(2-nitro-propenyl)-benzene

A stirred solution of 4-methylsulfanyl-benzaldehyde (5.0 g, 28.8 mmol)and ammonium acetate (0.666 g, 8.6 mmol) in nitroethane (17 ml, 236mmol) is heated at reflux for 5 hours. The solvent is removed and theresidue is dissolved in CHCl₃ (100 ml) and washed with water (100 ml)followed by brine (100 ml). After drying (MgSO₄) the solvent is removedto give the title compound as a yellow solid which is used crude in thenext step.

27b) 1-(4-Methylsulfanyl-phenyl)-propan-2-one

A stirred mixture of crude 1-methylsulfanyl-4-(2-nitro-propenyl)-benzene(27a) (28.8 mmol) iron filings (6.25 g, 112 mmol) and ferric chloridehexahydrate (0.155 g, 0.57 mmol) in water (20 ml) is heated to reflux.Concentrated hydrochloric acid (10 ml) is added over 2 hours the refluxcontinued for 4 hours. After 18 hours at room temperature the reactionis diluted with water and chloroform. The mixture is filtered throughcelite and the organic extract is separated. The aqueous extract isextracted with chloroform and the combined organic extracts are dried(MgSO₄). The solvent is removed and the residue is purified bychromatography on silica eluting with hexane-ethyl acetate (3:1) toafford the title compound (2.65 g).

27c)[4-Methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine

Using 1-(4-methylsulfanyl-phenyl)-propan-2-one (27b) andpyrazin-2-yl-thiourea (1a) in an analogous procedure described for thepreparation of4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide(Example 1b) affords the title compound.

27d)[5-(4-Methanesulfinyl-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine

Hydrogen peroxide solution (27% in water) (35 ml, 0.28 mmol) is added toa stirred suspension of[4-methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine(27c) (0.090 g, 0.28 mmol) in acetic acid (5 ml). After 30 minutes thereaction is diluted with water and brought to pH 10 by addition ofaqueous sodium hydroxide. The product is extracted with ethyl acetate(3×50 ml), the combined organic extracts are washed with brine (50 ml),dried (MgSO₄) and the solvent removed to give the title compound as anorange solid (0.03 g).

Example 28[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine

Oxone (Potassium peroxymonosulfate) (0.417 g, 0.77 mmol) is added to astirred solution of[4-methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine(27c) (0.05 g, 0.16 mmol) in acetone-water (9:1). After 2 hours at roomtemperature the solid precipitate is removed by filtration. The solid isdissolved in methanol, filtered to remove oxone and the solvent isremoved from the filtrate to afford the title compound as a yellow solid(0.022 g).

Example 29(6-Chloro-pyrazin-2-yl)-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amine

The title compound is prepared following the same route as Example 28,replacing 6-pyrazin-2-yl-thiourea with 6-chloro-pyrazin-2-yl-thiourea.

Example 30[5-(3-Chloro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-pyridin-3-yl-amine

The title compound is prepared starting from3-chloro-4-methanesulfonyl-benzaldehyde (prepared as described in WO01/49660 A1) and 3-pyridylthiourea following an analogous sequence ofreactions described for the preparation of[4-Methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine(27c) from 4-methylsulfanyl-benzaldehyde.

Example 31[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amine31a) 4-Methanesulfonyl-benzaldehyde

4-Chlorobenzaldehyde (5.0 g, 36 mmol) and methanesulfinic acid sodiumsalt (4.04 g, 40 mmol) are dissolved in dry DMSO under argon. Thestirred reaction mixture is heated at 100° C. for 17 hours then pouredonto water (50 ml). The white precipitate is removed by filtration anddried under vacuum to afford the title compound (2.2 g).

31b) 1-(4-Methanesulfonyl-phenyl)-propan-2-one

The title compound is prepared by the procedures described inexperiments 27a and 27b, replacing 4-methylsulfanyl-benzaldehyde with4-methanesulfonyl-benzaldehyde (31a).

31c)6-Chloro-pyridin-3-yl)-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amine

The title compound is prepared from1-(4-methanesulfonyl-phenyl)-propan-2-one (31b) and(6-chloro-pyridin-3-yl)-thiourea following the sequence of reactionsdescribed in Example 2.

31 d)[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amine

A stirred solution of N-methyl piperazine (0.184 g, 1.84 mmol) and(6-chloro-pyridin-3-yl)-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amine(31c) (0.070 g, 0.184 mmol) in DMSO (2 ml) is heated in a microwave(PROLABO SYNTHEWAVE s402™) at 60% power (180 W) for 10 hours. Thesolvent is removed and the residue is purified by chromatography onsilica eluting with ethyl acetate-methanol (9:1) to give the titlecompound as a yellow solid (0.096 g).

Further compounds of formula I which are also of formula XII are shownin Table 2 below, the method of preparation being described hereinafter.The table also shows mass spectrometry data. The Examples are in freeform.

TABLE 2 M/s Ex. R^(a) R^(b) R¹ MH+ 32 Cl

410.0  33 Cl

382.0  34 Cl

425.8  35 Cl

413.9  36 Cl

428.1  37 Cl

441.9  38 Cl

430.9  39 Cl

444.9  40 Cl

457.9  41 Cl

483.0  42 H

391.4  43 H

379.9  44 H

348.0  45 H

335.93 46 H

381.89 47

H

353.94 48

H

366.72 49

H

336.61 50

H

353.61 51

H

366.89 52

H

337.90 53

H

425.96 54

H

466.98 55

H

424.99 56

H

425.93 57

H

453.94 58

H

411.89 59

—CF₃

415.19 60

—CF₃

 402.855 61

—CF₃

492.94 62

—CF₃

546.4  63

—CF₃

519.01 64

—CF₃

505.98 65

—CF₃

449.04 66

—CF₃

513.23 67

—CF₃

534.24 68

F

352.91 69

F

366.91 70

F

432.86 71

442.98 72

400.93 73

463.04 74

433.06 75

432.99 76

413.01 77

427.02 78

441.00 79

456.23 80

488.92 81

464.27 82

H

300.97 83

H

312.97 84

H

331.95

Preparation of Specific Examples Example 32[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(6-methoxy-pyridin-3-yl)-amine32a) 2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride

To chlorosulfonic acid (25 ml, excess) cooled at −10° C. is addeddropwise 4-chlorophenyl acetone (1.0 g, 5.93 mmol). The temperature iskept below 0° C. throughout the addition. The reaction mixture is thenleft to warm up to room temperature overnight. The reaction mixture ispoured carefully onto ice (1500 ml). Once the ice is melted, the aqueouslayer is extracted with dichloromethane (3×250 ml). The combined organiclayers are dried over MgSO₄, filtered and concentrated to afford thetitled compound as an off-white solid.

32b) 1-(4-Chloro-3-methanesulfonyl-phenyl)-propan-2-one

To a stirred solution of sodium sulfite (0.5 g, 3.99 mmol) and sodiumhydrogen carbonate (0.34 g, 3.99 mmol) in water (10 ml) at 70° C. isadded a solution of 2-chloro-5-(2-oxo-propyl)-benzenesulfonyl chloride(32a) (0.5 g, 1.87 mmol) in 1,4-dioxane (20 ml). After 1 hour thereaction mixture is concentrated to yield the sulfinate intermediate. Tothe sulfinate intermediate (0.47 g, 1.95 mmol) in DMF (20 ml) is addediodomethane (0.12 ml, 1.95 mmol). After 1 hour at 40° C., the reactionmixture is poured into water (400 ml) and extracted with ethyl acetate(3×100 ml). The combined organic layers are dried over MgSO₄, filteredand concentrated. The residue is purified by chromatography on silica,eluting with hexane/ethyl acetate (4:1), then left overnight in thevacuum oven to afford the titled compound.

32c)[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(6-methoxy-pyridin-3-yl)-amine

1-(4-chloro-3-methanesulfonyl-phenyl)-propan-2-one (32b) (0.23 g, 1mmol) is dissolved in dioxan (10 ml) and the solution is cooled to 10°C. at which point the mixture is semi-frozen. Bromine (0.045 ml, 0.8mmol, 0.8 eq.) is added slowly and the mixture is stirred for anadditional 15 minutes in a semi frozen state. The mixture is thenallowed to warm to room temperature and the solvent is removed to give abrown oil containing starting material and1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. Thismaterial is dissolved in ethanol (10 ml).(6-Methoxy-pyridine-3-yl)-thiourea (0.183 g, 1 mmol) is added in oneportion. The mixture is stirred at 60° C. for 30 minutes then allowed tocool whereupon the product crystallised. Filtration affords the titledcompound as a white solid.

Example 332-Chloro-5-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide33a) 2-Chloro-5-(2-oxo-propyl)-benzenesulfonamide

2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (32a) (2.0 g, 7.5mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate(7.5 ml, 2M solution, 2 eq.) is added followed by a solution of ammoniain dioxan (37.5 ml, 0.5 M). After 30 min the reaction mixture is pouredonto water (250 ml) and extracted with ethyl acetate (3×100 ml). Thecombined organic extracts are washed with water (2×100 ml) followed bybrine (100 ml) and dried (MgSO₄). After filtration the solvent isremoved and the product is purified by chromatography on silica, elutingwith ethyl acetate/hexane (1:2) to afford the titled compound.

33b) 5-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide

A stirred solution of 2-chloro-5-(2-oxo-propyl)-benzenesulfonamide (33a)(1.4 g, 5.7 mmol) in dry THF (100 ml) at room temperature is treatedwith polymer supported pyridine hydrobromide perbromide (2.9 g, 5.7mmol) and left to stir overnight. The reaction mixture is then filteredand the solvent removed in vacuo. The residue is purified bychromatography on silica eluting with 1:4 ethyl acetate-hexane to givethe titled compound.

33c)2-Chloro-5-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

Pyrazin-2-yl-thiourea (1a) (0.07 g, 0.57 mmol) is added to a stirredsolution of 5-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (33b)(0.15 g, 0.46 mmol) in 1,4-dioxan (10 ml) at room temperature. Thereaction mixture is heated to 70° C. for 2 h. The resulting precipitateis removed by filtration and dried under vacuum to give the titledcompound

Example 342-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by the same procedure as Example 33,replacing ammonia in this procedure with ethanolamine.

Example 352-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide35a) (1H-Pyrazol-3-yl)-thiourea

1H-Pyrazol-3-ylamine (9.5 g, 114 mmol) is added to a stirred solution ofbenzoyl isothiocyanate (19.6 g, 120 mmol) in DMF (100 ml) at roomtemperature. The solution is heated at 100° C. for 30 minutes, allowedto cool and poured onto water (1000 ml). The yellow suspension of1-benzoyl-3-(1H-pyrazol-3-yl)-thiourea is removed by filtration andwashed with water. This material is dissolved in 2M aqueous sodiumhydroxide (120 ml) and the solution is heated at reflux for 30 minutes.After cooling to room temperature the solution is brought to pH 4 byaddition of 3M aqueous HCl and extracted with ethyl acetate. The organicextract is dried (MgSO₄) and concentrated to afford the titled compoundwhich is removed by filtration and recrystallised from dichloromethane.

35b)2-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by an analogous procedure to Example 34,replacing pyrazin-2-yl-thiourea in this procedure with(1H-pyrazol-3-yl)-thiourea (35a).

Example 362-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(1-methyl-1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide36a) (1-Methyl-1H-pyrazol-3-yl)-thiourea

This material is prepared from 1-methyl-1H-pyrazol-3-ylamine followingthe procedure described for the preparation of(1H-pyrazol-3-yl)-thiourea (35a)

36b)2-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(1-methyl-1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by an analogous procedure to Example 34,replacing pyrazin-2-yl-thiourea (1a) in this procedure with(1-methyl-1H-pyrazol-3-yl)-thiourea (36a)

Example 372-Chloro-5-[2-(2,5-dimethyl-2H-pyrazol-3-ylamino)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide37a) (2,5-Dimethyl-2H-pyrazol-3-yl)-thiourea

This material is prepared from 2,5-dimethyl-2H-pyrazol-3-ylaminefollowing the procedure described for (1H-pyrazol-3-yl)-thiourea (35a)

37b)2-Chloro-5-[2-(2,5-dimethyl-2H-pyrazol-3-ylamino)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide

The titled compound is prepared by an analogous procedure to Example 34,replacing pyrazin-2-yl-thiourea (1a) in this procedure with(2,5-dimethyl-2H-pyrazol-3-yl)-thiourea (37a).

Example 382-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(thiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide38a) Thiazol-2-yl-thiourea

Aminothiazole (1.0 g, 10 mmol is added in small portions to a stirredsolution of FMOC isothiacyanate (2.92 g, 10.4 mmol) in dichloromethane(30 ml). The reaction mixture is stirred at room temperature for 18hours. The solid material which precipitates is removed by filtrationand dissolved in a solution containing 20% piperidine in methanol (10ml). After stirring for 18 hours at room temperature the mixture isfiltered and the solvent is removed from the filtrate. The residue isdissolved in ethyl acetate and washed with 2M aqueous HCl (3×40 ml). Theorganic layer is then separated and extracted with saturated aqueoussodium bicarbonate (3×30 ml). The aqueous extract is acidified with 2MHCl and the product is extracted into ethyl acetate. The organic extractis dried (MgSO₄), filtered and the solvent removed to give the titledcompound as a white solid.

38b)2-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(thiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by an analogous procedure to Example 34,replacing pyrazin-2-yl-thiourea in this procedure withthiazol-2-yl-thiourea (38a).

Example 392-Chloro-N-(2-hydroxy-ethyl)-5-[4-methyl-2-(5-methyl-thiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by the method described in Example 34,replacing pyrazin-2-yl-thiourea (1a) with(5-methyl-thiazol-2-yl)-thiourea. This thiourea is prepared by ananalogous procedure to thiazol-2-thiourea (38a)

Example 402-Chloro-N,N-bis-(2-hydroxy-ethyl)-5-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by the same procedure as Example 35,replacing ethanolamine in this procedure with2-(2-hydroxy-ethylamino)-ethanol.

Example 412-Chloro-N-(3-diethylamino-propyl)-5-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by the same procedure as Example 35,replacing ethanolamine in this procedure withN,N-diethyl-propane-1,3-diamine

Example 42N-(2-Hydroxy-ethyl)-3-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzene-sulfonamide42a) 1-Bromo-1-(3-nitro-phenyl)-propan-2-one

A stirred solution of 3-nitrophenylacetone (2.5 g, 14.0 mmol) in dry THF(50 ml) at room temperature is treated with polymer supported pyridinehydrobromide perbromide (7.0 g, 14.0 mmol) and left to stir overnight.The reaction mixture is then filtered and the solvent removed in vacuo.The residue is purified by chromatography on silica eluting with 1:4ethyl acetate-hexane to give the titled compound

42b) [4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine

The titled compound is prepared by the same procedure described for thepreparation of 33c, replacing5-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (33b) in thisprocedure with 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (42a)

42c) 3-[4-Methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonylchloride

[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (42b)(1.079 g, 3.4 mmol) is dissolved in ethyl acetate/THF (5/1, 240 ml) andstirred at room temperature under an atmosphere of argon. The solutionis then treated with 10% Pd/C (1.1 g). The reaction mixture is purgedthree times with nitrogen and placed under an atmosphere of hydrogenovernight. The mixture is then filtered through celite and the catalystis washed with THF (200 ml). The solvent is removed in vacuo to leave[5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (0.351 g,36%). MH⁺ (ESMS):283.5

Concentrated sulfuric acid (1 ml) is added slowly to a stirred solutionof [5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (0.351g, 1.24 mmol) in acetic acid (20 ml) at 10° C. A solution of sodiumnitrite (0.09 g, 1.24 mmol) in water (0.5 ml) is added dropwise. After10 minutes a solution of the reagent (SO₂/AcOH/CuCl₂/H₂O) (50 ml) at 0°C. is added and the mixture is allowed to warm to room temperature andstirred for overnight. The mixture is diluted with water (100 ml) andextracted with ethylacetate (3×100 ml). The organic extracts arecombined, washed with brine (100 ml), dried (MgSO₄), filtered and thesolvent is removed to afford the title compound (0.251 g, 55%) which isused crude in the subsequent reaction.

42d)N-(2-Hydroxy-ethyl)-3-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

3-[4-Methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonyl chloride(42c) (0.251 g, 0.68 mmol) is dissolved in dioxane (10 ml). The solutionis treated with 2M aqueous sodium carbonate (0.7 ml, 1.36 mmol) followedby the addition of ethanolamine (0.125 ml, 2.05 mmol). The reactionmixture is stirred overnight. The solvent is removed in vacuo and theresidue is taken into water (10 ml)/ethylacetate (30 ml) and sonicated.The layers are separated then the aqueous layer is extracted with ethylacetate (2×30 ml). The combined organic layers are dried over MgSO₄,filtered and concentrated to give a residue which is purified by prepLC-MS to give the titled compound (0.038 g, 14%)

Example 43N-(2-Hydroxy-ethyl)-3-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide43a) 2-Chloro-N-(2-hydroxy-ethyl)-5-(2-oxo-propyl)-benzenesulfonamide

This material is prepared from 2-chloro-5-(2-oxopropyl)-benzenesulphonylchloride (32a) following the same procedure described for thepreparation of 2-chloro-5-(2-oxo-propyl)-benzenesulfonamide (33a),replacing ammonia in this procedure with ethanolamine.

43b) N-(2-Hydroxy-ethyl)-3-(2-oxo-propyl)-benzenesulfonamide

2-Chloro-N-(2-hydroxy-ethyl)-5-(2-oxo-propyl)-benzenesulfonamide (43b)(1.22 g, 4.18 mmol) in methanol (150 ml) is stirred under an atmosphereof hydrogen in the presence of 10% Palladium on carbon (1 g) for 5 hoursat room temperature. Filtration through celite and removal of thesolvent affords the titled compound which is purified by chromatographyon silica eluting with ethyl acetate-hexane (2:1).

43c)N-(2-Hydroxy-ethyl)-3-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound was prepared fromN-(2-hydroxy-ethyl)-3-(2-oxo-propyl)-benzenesulfonamide (43b) followingthe two-step procedure (bromination, thiazole formation) described forthe conversion of 2-chloro-5-(2-oxo-propyl)-benzene-sulfonamide (33a) to2-chloro-5-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide(33c) replacing pyrazin-2-yl-thiourea (1a) in the final step with(1H-pyrazol-3-yl)-thiourea (35a).

Example 443-[4-Methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide

The titled compound is prepared by an analogous procedure toN-(2-hydroxy-ethyl)-3-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide(Example 42 using ammonia in place of ethanolamine in the final step.

Example 45 and 46

The compounds of these Examples, namely3-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamideand3-[2-(5-ethyl-[1,3,4]thiadiazol-2-ylamino)-4-methyl-thiazol-5-yl]-benzenesulfonamiderespectively are prepared by the route described forN-(2-hydroxy-ethyl)-3-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide(Example 43) using the appropriate amine and thiourea. The thiourea usedin Example 46 is prepared by an analogous procedure tothiazol-2-yl-thiourea Example (38a).

Examples 47 to 58

The compounds of these Examples, namely4-[4-methyl-2-([1,3,4]thiadiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,4-[4-methyl-2-(5-methyl-thiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,4-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzenesulfonamide,4-[4-methyl-2-(thiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,4-[4-methyl-2-(4-methyl-thiazol-2-ylamino)-thiazol-5-yl]-benzenesulfonamide,4-[4-methyl-2-(1H-tetrazol-5-ylamino)-thiazol-5-yl]-benzenesulfonamideand4-[2-(5-ethyl-[1,3,4]thiadiazol-2-ylamino)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamiderespectively are prepared in a three step sequence from4-(2-oxo-propyl)-benzenesulfonyl chloride (prepared as described inEuropean patent specification EP 91749 A2) following the proceduresdescribed in Example 1, using the appropriate amines and thioureas.Thioureas used in Examples 47, 48, 50, 51 & 53 are prepared from theappropriate amino heterocycle using the FMOC procedure described forthiazol-2-yl-thiourea (Example 38a) Thioureas used in Examples 49 and 52are prepared as described for (1H-pyrazol-3-yl)-thiourea (35a). Thepreparation of thioureas used in Examples 54, 55, 56, 57 & 58 aredescribed for each of these Examples.

Example 544-{4-Methyl-2-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-ylamino]-thiazol-5-yl}-benzenesulfonamide54a) 5-(2-Chloro-ethyl)-[1,3,4]thiadiazol-2-ylamine

Thiosemicarbazide (10 g, 111 mmol) is added in portions to a solution of3-chloropropionic acid (10 g, 92 mmol) in concentrated sulfuric acid.The mixture is heated with stirring at 75° C. for 1 hour. After coolingto room temperature the reaction mixture id added slowly to water andthe resulting solution is brought to pH 7 by addition of aqueous ammoniasolution. The titled product precipitates as a yellow solid which isremoved by filtration and dried.

54b) 5-(2-Morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-ylamine

A mixture of 5-(2-chloro-ethyl)-[1,3,4]thiadiazol-2-ylamine (54a) (2.5g, 15.3 mmol), morpholine (2.67 g, 30 mmol) and sodium iodide (0.15 g)is heated with stirring in toluene at 80° C. After adding triethylamine(2.13 ml, 15.3 mmol) heating is continued for an additional 4 hours. Thesolvent is removed and the residue is partitioned between water (pH 13)and n-butanol. The organic extract is dried (MgSO₄) and the solid isremoved to afford the titled compound as a yellow solid.

54c) [5-(2-Morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl}-thiourea

The titled compound is prepared from5-(2-Morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-ylamine (54b) followingthe procedure described for (1H-pyrazol-3-yl)-thiourea (35a)

54d)4-{4-Methyl-2-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-ylamino]-thiazol-5-yl}-benzenesulfonamide

The titled compound is prepared from 4-(2-oxo-propyl)-benzenesulfonylchloride (prepared as described in European patent specification EP91749 A2) following the procedures described in Example 1, using ammoniaand [5-(2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl}-thiourea (54c).

Example 554-{2-[5-(2-Dimethylamino-ethyl)-[1,3,4]thiadiazol-2-ylamino]-4-methyl-thiazol-5-yl}-benzenesulfonamide

The titled compound is prepared following the procedures described inExample 54, replacing morpholine in the above procedures withdimethylamine.

Example 563-{5-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-propionicacid 56a) 3-(5-Amino-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester

3-Chlorocarbonyl-propionic acid methyl ester (4.4 g, 21 mmol) is addeddropwise to a stirred suspension of thiosemicarbazide (4.0 g, 44 mmol)in THF (25 ml) at 0° C. After stirring at room temperature for 18 h theproduct which precipitates is removed by filtration and washed withdiethyl ether. This product (7.1 g, 34 mmol) is suspended in toluene (30ml) at 0° C. and methane sulfonic acid (3.37 ml, 52 mmol) is addeddropwise to the stirred reaction. The reaction is heated at 70° C. for 3hours then concentrated at reduced pressure. Methanol (30 ml) is addedfollowed by slow addition of aqueous ammonia, with stirring, until thesolution is basic. The titled compound which precipitates is removed byfiltration and purified by chromatography on silica, eluting withchloroform-methanol (10:1).

56b) 3-(5-Thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid

Ethoxycarbonyl isothiocyanate (0.656 ml, 5.61 mmol) is added dropwise toa stirred suspension of 3-(5-amino-[1,3,4]thiadiazol-2-yl)-propionicacid methyl ester (56a) in dichloromethane (30 ml). The reaction is atroom temperature for 18 hours. After removing the solvent, aqueoussodium hydroxide (2M, 10 ml) is added and the stirred mixture is heatedat reflux for 3 hours. The solution is allowed to cool to roomtemperature and brought to pH 3 by the addition of 6M aqueous HCl. Thetitled compound which precipitates is removed by filtration, washed withethyl acetate and dried in vacuo.

56c)3-{5-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-propionicacid

The titled compound is prepared from3-(5-thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid (56b) and from4-(2-oxo-propyl)-benzenesulfonyl chloride (prepared as described inEuropean patent specification EP 91749 A2) following proceduresdescribed for Example 1 using ammonia to prepare the sulfonamide.

Example 573-{5-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-propionicacid ethyl ester

The titled compound is obtained as a minor component during the finalstep in the preparation of3-{5-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-propionicacid (56c). This involves formation of (56c) in ethanol at reflux in thepresence of anhydrous HBr which is generated during the reaction.

Example 58{5-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-aceticacid

The titled compound is prepared by an analogous procedure to3-{5-[4-methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-propionicacid Example (46) using methyl malonyl chloride in place of3-chlorocarbonyl-propionic acid methyl ester in the first step.

Example 59[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine59a) 4-Methanesulfonyl-3-trifluoromethyl-benzaldehyde

Methane sulfinic acid sodium salt (6.65 g, 65.1 mmol) is added to astirred solution of 4-Fluoro-3-trifluoromethyl-benzaldehyde (10.0 g,52.1 mmol) in dry DMSO (200 ml) and the mixture is heated at 75° C.After 2 hours the reaction is allowed to cool and poured onto ice-water(300 ml). The precipitate is collected by filtration, washed with waterand dissolved in dichloromethane (200 ml). The organic extract is washedwith water (3×200 ml), dried over MgSO₄, filtered, and the solvent isremoved to give the title compound as a white solid.

59b) 1-Methanesulfonyl-4-(2-nitro-propenyl)-2-trifluoromethyl-benzene

A stirred mixture of 4-methanesulfonyl-3-trifluoromethyl-benzaldehyde(Example 5001a) (12 g, 47 mmol), nitroethane (27.5 ml, 380 mol) andammonium acetate (1.22 g, 16 mmol) is heated at reflux under argon for18 hours. The mixture is concentrated to give an oil which is dissolvedin dichloromethane (200 ml) and washed with water (3×200 ml), followedby brine (200 ml). The organic extract is dried (MgSO₄), filtered andthe solvent removed to give the product as red oil. This is usedimmediately in the next step.

59c) 1-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-propan-2-one

A solution of freshly prepared1-methanesulfonyl-4-(2-nitro-propenyl)-2-trifluoromethyl-benzene (59b)(14 g, 45 mmol) in acetic acid (100 ml) is added slowly to a stirredslurry of Iron powder (27.6 g, 495 mmol) in acetic acid (100 ml) at 60°C. The reaction is then stirred at 100° C. for 2 hours then allowed tocool and poured onto ice-water (300 ml). After filtration throughcelite, washing with dichloromethane (500 ml), the organic extract isseparated and washed with water (3×300 ml) followed by brine (500 ml).The organic extract is dried (MgSO₄) and concentrated to give a red oil.Chromatography on silica, eluting with ethyl acetate-hexane, affords thetitled compound as a white solid.

59d)[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine

1-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-propan-2-one (Example59c) (0.60 g, 2.14 mmol) is dissolved in dioxan (50 ml) and the solutionis cooled to 10° C. at which point the mixture is semi frozen. Bromine(0.088 ml, 1.7 mmol) is added slowly and the mixture is stirred for anadditional 30 min in a semi frozen state. The mixture is then allowed towarm to room temperature and the solvent is removed to give a brown oil.This material is dissolved in ethanol and pyrazin-2-yl-thiourea (1a) isadded in one portion. The mixture is stirred at 60° C. for 30 minutesthen allowed to cool whereupon the titled product precipitates and isremoved by filtration.

Example 60[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine

The titled compound is prepared by an analogous procedure to Example 50,replacing pyrazin-2-yl-thiourea (1a) with (1H-pyrazol-3-yl)-thiourea(3402a).

Example 613-{5-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-propionicacid

The titled compound is prepared by an analogous procedure to Example 59,replacing pyrazin-2-yl-thiourea (1a) with3-(5-thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid (56b)

Example 624-{5-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamino]-[1,3,4]thiadiazol-2-yl}-cyclohexanecarboxylicacid

The titled compound is prepared by an analogous procedure to Example 59,replacing pyrazin-2-yl-thiourea (1a) with4-(5-thioureido-[1,3,4]thiadiazol-2-yl)-cyclohexane-carboxylic acid.This thiourea is prepared in an identical procedure to3-(5-thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid (56b),substituting 3-chlorocarbonyl-propionic acid methyl ester for4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester in the firststep.

Example 63[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-[5-(4-methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-yl]-amine63a) 5-Bromo-[1,3,4]thiadiazol-2-ylamine

Bromine (2.1 ml, 41.5 mmol) is added to a stirred solution of2-amino-1,3,4-thiadiazole (2.8 g, 27.7 mmol) in methanol (100 ml). After18 hours the solvent is removed and the residue is partitioned betweenethyl acetate (100 ml) and aqueous NaOH (1M, 100 ml). The organicextract is separated, washed with brine (100 ml) and dried over MgSO₄.The solvent is removed to afford the titled compound.

63b) 5-(4-Methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-ylamine

A mixture of 1-methylpiperazine (0.742 ml, 6.6 mmol) andbromo-[1,3,4]thiadiazol-2-ylamine (63a) (0.60 g, 3.3 mmol) in n-propanol(15 ml) is heated at reflux for 6 hours. After cooling to roomtemperature the solvent is removed and the residue is trituated withethyl acetate and methanol to afford the required compound as a pinksolid.

63c) [5-(4-Methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-yl]-thiourea

Ethoxycarbonylisothiocyanate (0.346 ml, 2.96 mmol) is added dropwise toa stirred suspension of5-(4-Methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-ylamine (63b) (0.59 g,2.96 mmol) in acetonitrile (15 ml) and DMF (5 ml). The reaction isheated at 80° C. for 7 h followed by removal of the solvent. The residueheated in 2M aqueous NaOH (80 ml) at reflux for 30 minutes. Aftercooling to room temperature the solution is neutralised by addition of6M aqueous HCl and the titled product is removed by filtration and driedunder vacuum.

63d)[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-[5-(4-methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-yl]-amine

The titled compound is prepared by an analogous procedure to Example 59,replacing pyrazin-2-yl-thiourea (1a) with[5-(4-methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-yl]-thiourea (63c).

Example 64[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-(5-morpholin-4-yl-[1,3,4]thiadiazol-2-yl)-amine

The titled compound is prepared by an analogous procedure to Example 63,substituting 1-methyl-piperazine for morpholine.

Example 65(6-Chloro-pyrazin-2-yl)-[5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-amine

The titled compound is prepared from1-(4-methanesulfonyl-3-trifluoromethyl-phenyl) propan-2-one (59c) and6-chloro-pyrazin-2-yl-thiourea.

Example 66[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-amine

The titled compound is prepared from(6-chloro-pyrazin-2-yl)-[5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-amine(65) and 1-methyl piperazine following the procedure described inExample 13.

Example 67[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-[5-(2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amine

The titled compound is prepared by an analogous procedure to Example 54,replacing 4-(2-oxo-propyl)-benzenesulfonamide with1-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propan-2-one (59c).

Example 68[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl-amine68a) 3-Fluoro-4-methanesulfonyl-benzaldehyde

Methane sulfinic acid sodium salt (22.65 g, 220 mmol) is added to astirred solution of 3,4-difluorobenzaldehyde (25 g, 175 mmol) in dryDMSO (200 ml). The mixture is heated at 65-70° C. for 5 hours thenpoured onto ice-water (500 ml). The precipitate is filtered, washed withwater and dissolved in chloroform (400 ml). The organic extract iswashed with water (2×200 ml), dried over MgSO₄, filtered andconcentrated to give the titled compound as a white solid.

68b) 2-Fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene

A stirred mixture of 3-fluoro-4-methanesulfonyl-benzaldehyde (Example68a) (20 g, 99 mmol), nitroethane (58 ml, 811 mmol) and ammonium acetate(2.29 g, 29 mmol) is heated at reflux (115° C.) under argon for 18hours. The mixture is concentrated to give an oil which is dissolved inchloroform (200 ml) and washed with water (2×200 ml), followed by brine(100 ml). The organic extract is dried (MgSO₄), filtered and the solventremoved to give the product as an orange oil. This is used immediatelyin the next step.

68c) 1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one

Freshly prepared 2-fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene(Example 68b) (20 g, 77 mmol) in glacial acetic acid (150 ml) is addedslowly in 15×10 ml portions to a stirred slurry of iron powder (46 g,833 mmol) in glacial acetic acid (150 ml) at 60° C. The reaction mixtureis heated at 100° C. for an additional 2 hours, allowed to cool to roomtemperature and poured on to ice water (600 ml). The mixture is filteredthrough celite to remove iron residues, washing with dichloromethane(300 ml). The organic layer is removed and the aqueous solution isextracted with more DCM (3×200 ml). The combined organic extracts aredried (MgSO₄), filtered and concentrated to a red solution. The titledproduct crystallises from this solution on standing.

68d)[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine

1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (68c) (6.0 g, 26mmol) is dissolved in dioxan (50 ml) and the solution is cooled to 10°C. at which point the mixture is semi frozen. A solution of bromine (0.9ml, 17 mmol) in chloroform (2 ml) is added slowly over 30 minutes andthe mixture is stirred for an additional 15 minutes in a semi frozenstate. The mixture is then allowed to warm to room temperature and thesolvent is removed to give a red oil. Ethanol (70 ml) and(1H-pyrazol-3-yl)-thiourea (35a) (3.2 g, 22 mmol) are added and thereaction is stirred at 60° C. for 30 minutes. The solution is allowed tocool to room temperature whereupon the product crystallises. Filtrationaffords the titled compound.

Example 69[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-methyl-1H-pyrazol-3-yl)-amine

The titled material is prepared by an analogous procedure to Example 68,replacing (1H-pyrazol-3-yl)-thiourea (35a) in this procedure with(1-methyl-1H-pyrazol-3-yl)-thiourea (36a).

Example 70(4-Bromo-1H-pyrazol-3-yl)-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amine

Bromine (0.012 ml, 0.23 mmol) in chloroform (0.5 ml) is added dropwiseto a stirred solution of[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine(69) (0.10 g, 0.23 mmol) in chloroform (1 ml) and methanol (2 ml). Afterstirring at room temperature for 1 hour the hydrobromide salt of thetitled compound precipitates. This is removed by filtration and washedwith ether.

Example 71{5-[4-Methanesulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]4-methyl-thiazol-2-yl}-(1H-pyrazol-3-yl)-amine

A stirred mixture of[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-aminehydrobromide salt (68d) (1.0 g, 2.3 mmol), Caesium carbonate (1.50 g,4.6 mmol) and 2-propylamidazole (0.508 g, 4.6 mmol) in dry DMSO (10 ml)is heated at 140° C. for 6 hours. After cooling to room temperature themixture is diluted with ethyl acetate (50 ml) and washed with water (100ml). The organic extract is separated and the crude product is absorbedon silica. Purification by chromatography on silica, eluting with ethylacetate-ethanol (1:1) affords the titled compound.

Examples 72-81

The compounds of these Examples, namely[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine,N,N-diethyl-N′-(2-methanesulfonyl-5-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-phenyl)-N′-methyl-ethane-1,2-diamine,{5-[4-methanesulfonyl-3-(4-methyl-piperazin-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-(1H-pyrazol-3-yl)-amine,[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(5-methyl-[1,3,4]thiadiazol-2-yl)-amine,[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine,(5-[4-methanesulfonyl-3-(2-methyl-imidazol-1-yl)-phenyl]4-methyl-thiazol-2-yl)-pyrazin-2-yl-amine,{5-[3-(2-ethyl-imidazol-1-yl)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-pyrazin-2-yl-amine,{5-[3-(2-isopropyl-imidazol-1-yl)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-pyrazin-2-yl-amine,(5-ethyl-[1,3,4]thiadiazol-2-yl)-(5-[4-methane-sulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl)-amineand{5-[4-methanesulfonyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-4-methyl-thiazol-2-yl}-(1H-pyrazol-3-yl)-aminerespectively, are prepared from the appropriate amine or alcohol andfluorinated phenyl-aminothiazole following the procedure described inExample 71 and using a reaction temperature of 100 to 150° C. Thefluorinated phenyl-amino-thiazoles used in these Examples are preparedfrom 1-(3-fluoro-4-methane-sulfonyl-phenyl)-propan-2-one (Example 68c)and the appropriate thiourea following the procedure described inExample 68d.

Examples 82 to 84

The compounds of these Examples, namely4-[4-methyl-2-(1H-pyrazol-3-ylamino)-thiazol-5-yl]-benzoic acid,4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzoic acid and4-[4-methyl-2-(5-methyl-thiazol-2-ylamino)-thiazol-5-yl]-benzoic acidare prepared from 4-(2-oxo-propyl)benzoic acid and the appropriateaminothiazole following the bromination-thiazole formation proceduresdescribed in Example 65.

1. A compound of formula I

in free or salt form, wherein R¹ is a 5 or 6-membered heterocyclic ringcontaining nitrogen and optionally one or more further hetero atomsselected from the group consisting of nitrogen, oxygen and sulphur, thatring being optionally substituted by halo, C₁-C₈-alkyl optionallysubstituted by —NR⁶R⁷, carboxy, C₁-C₈-alkoxycarbonyl or a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur, thatring being optionally substituted by C₁-C₈-alkoxy, —NR⁶R⁷,C₃-C₈-cycloalkyl optionally substituted by carboxy, or a 5 or 6-memberedheterocyclic ring containing at least one hetero atom selected from thegroup consisting of nitrogen and oxygen, that ring being optionallysubstituted by C₁-C₈-alkyl; R² is C₁-C₈-alkyl or halo; R³ is —SO₂NR⁸R⁹,—SOR¹⁰ or —SO₂R¹¹ and is in the para or meta position with respect tothe indicated thiazole ring; R⁴ and R⁵ are each independently hydrogen,C₁-C₈-alkyl, C₁-C₈-alkoxy optionally substituted by a 5 or 6-memberedheterocyclic ring containing at least one hetero atom selected from thegroup consisting of nitrogen, oxygen and sulphur, that ring beingoptionally substituted by halo, halo-C₁-C₈-alkyl, cyano, —SO₂NH₂,carboxy, amino, amino-C₁-C₈-alkyl, di(C₁-C₈-alkyl)amino-C₁-C₈-alkyl,amino-C₁-C₈-alkoxy, di(C₁-C₈-alkyl)amino-C₁-C₈-alkoxy, aminocarbonyl,C₁-C₈-alkylaminocarbonyl, di(C₁-C₈-alkyl)aminocarbonyl, —NR¹²R¹³,carboxy-C₁-C₈-alkyl, carboxy-C₁-C₈-alkoxy, R¹⁴, —OR¹⁴ or a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl; R⁶ is hydrogen orC₁-C₈-alkyl; R⁷ is C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, di(C₁-C₈-alkyl)amino or a 5 or 6-membered heterocyclicring containing at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulphur, that ring being optionallysubstituted by C₁-C₈-alkyl; R⁸ is hydrogen or C₁-C₈-alkyl optionallysubstituted by hydroxy, C₁-C₈-alkoxy, cyano, amino, C₁-C₈-alkylamino,di(C₁-C₈-alkyl)amino or a 5 or 6-membered heterocyclic ring having oneor more ring hetero atoms selected from the group consisting of oxygen,nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl; R⁹ is hydrogen, C₁-C₈-alkyl optionally substituted byhydroxy, or C₃-C₈-cycloalkyl; R¹⁰ is C₁-C₈-alkyl; R¹¹ is C₁-C₈-alkyloptionally substituted by halogen, hydroxy, C₁-C₈-alkoxy, cyano, amino,C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino; R¹² is hydrogen orC₁-C₈-alkyl; R¹³ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl optionallysubstituted by hydroxy, amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)aminoor R¹² and R¹³ together with the nitrogen atom to which they areattached form a 5 or 6-membered saturated or unsaturated heterocyclicring that contains one or more further hetero atoms selected from thegroup consisting of oxygen, nitrogen and sulphur, that ring beingoptionally substituted by C₁-C₈-alkyl; and R¹⁴ is C₁-C₈-alkyl optionallysubstituted by hydroxy or —NR¹²R¹³.
 2. A compound according to claim 1,in free or salt form, wherein R¹ is a 5 or 6-membered heterocyclic ringcontaining nitrogen and optionally one or more further hetero atomsselected from the group consisting of nitrogen, oxygen and sulphur, thatring being optionally substituted by halo, C₁-C₈-alkyl optionallysubstituted by —NR⁶R⁷, carboxy, C₁-C₈-alkoxycarbonyl or a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur,C₁-C₈-alkoxy, —NR⁶R⁷, C₃-C₈-cycloalkyl optionally substituted bycarboxy, or a 5 or 6-membered heterocyclic ring containing at least onehetero atom selected from the group consisting of nitrogen and oxygen,that ring being optionally substituted by C₁-C₈-alkyl; R² isC₁-C₈-alkyl; R³ is —SO₂NR⁸R⁹, —SOR¹⁰, or —SO₂R¹¹ and is in the para ormeta position with respect to the indicated thiazole ring; R⁴ ishydrogen, C₁-C₈-alkoxy optionally substituted by a 5 or 6-memberedheterocyclic ring containing at least one hetero atom selected from thegroup consisting of nitrogen, oxygen and sulphur, that ring beingoptionally substituted by halo, halo-C₁-C₈-alkyl, —SO₂NH₂, —NR¹²R¹³ or a5 or 6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl; R⁵ is hydrogen; R⁶ ishydrogen or C₁-C₈-alkyl; R⁷ is C₁-C₈-alkyl optionally substituted byhydroxy, di(C₁-C₈-alkyl)amino or a 5 or 6-membered heterocyclic ringcontaining at least one hetero atom selected from the group consistingof nitrogen and oxygen, that ring being optionally substituted byC₁-C₈-alkyl; R⁸ is hydrogen or C₁-C₈-alkyl optionally substituted bydi(C₁-C₈-alkyl)amino; R⁹ is hydrogen, C₁-C₈-alkyl optionally substitutedby hydroxy, or C₃-C₈-cycloalkyl; R¹⁰ is C₁-C₈-alkyl; R¹¹ is C₁-C₈-alkyl;R¹² is C₁-C₈-alkyl; and R¹³ is C₁-C₈-alkyl optionally substituted bydi(C₁-C₈-alkyl)amino.
 3. A compound according to claim 2, in free orsalt form, wherein R¹ is a 5 or 6-membered heterocyclic ring containingnitrogen and optionally one or more further hetero atoms selected fromthe group consisting of nitrogen, oxygen and sulphur, that ring beingoptionally substituted by halo, C₁-C₄-alkyl optionally substituted by—NR⁶R⁷, carboxy, C₁-C₄-alkoxycarbonyl or a 5 or 6-membered heterocyclicring containing at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulphur, C₁-C₄-alkoxy, —NR⁶R⁷,C₃-C₆-cycloalkyl optionally substituted by carboxy, or a 5 or 6-memberedheterocyclic ring containing at least one hetero atom selected from thegroup consisting of nitrogen and oxygen, that ring being optionallysubstituted by C₁-C₄-alkyl; R² is C₁-C₄-alkyl; R³ is —SO₂NR⁸R⁹, —SOR¹⁰,—SO₂R¹¹ and is in the para or meta position with respect to theindicated thiazole ring; R⁴ is hydrogen, C₁-C₄-alkoxy optionallysubstituted by a 5 or 6-membered heterocyclic ring containing at leastone hetero atom selected from the group consisting of nitrogen, oxygenand sulphur, that ring being optionally substituted by halo,halo-C₁-C₄-alkyl, —SO₂NH₂, —NR¹²R¹³ or a 5 or 6-membered heterocyclicring containing at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulphur, that ring being optionallysubstituted by C₁-C₄-alkyl; R⁵ is hydrogen; R⁶ is hydrogen orC₁-C₄-alkyl; R⁷ is C₁-C₄-alkyl optionally substituted by hydroxy,di(C₁-C₄-alkyl)amino or a 5 or 6-membered heterocyclic ring containingat least one hetero atom selected from the group consisting of nitrogenand oxygen, that ring being optionally substituted by C₁-C₄-alkyl; R⁸ ishydrogen or C₁-C₄-alkyl optionally substituted by di(C₁-C₄-alkyl)amino;R⁹ is hydrogen, C₁-C₄-alkyl optionally substituted by hydroxy, orC₃-C₅-cycloalkyl; R¹⁰ is C₁-C₄-alkyl; R¹¹ is C₁-C₄-alkyl; R¹² isC₁-C₄-alkyl; and R¹³ is C₁-C₄-alkyl optionally substituted bydi(C₁-C₄-alkyl)amino.
 4. A compound according to claim 1, which is alsoa compound of formula XII

wherein R^(a), R^(b) and R¹ are as shown in the following table: R^(a)R^(b) R¹ —SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

—SO₂NH₂ H

H

H

H

H

—OCH₃ —SO₂NH₂

—SO₂NH₂ Cl

—SO₂NH₂ Cl

—SO₂NH₂ H

—SO₂NH₂ H

H

H

H

Cl

H

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

—CF₃

—CF₃

—CF₃

—CF₃

—CF₃

—CF₃

—CF₃

—CF₃

—CF₃

F

F

F


5. A pharmaceutical composition comprising a compound according to claim1, optionally together with a pharmaceutically acceptable diluent orcarrier.
 6. A pharmaceutical composition according to claim 5 furthercomprising one or more anti-inflammatory, bronchodilatory orantihistamine drug substances, wherein the anti-inflammatory drugsubstance is selected from the group consisting of steroids, LTB4antagonists, LTD4 antagonists, dopamine receptor agonists and PDE4inhibitors; the bronchodilatory drug substance is selected from thegroup consisting of anticholinergic agents, antimuscarinic agents andbeta-2 adrenoceptor agonists; and the antihistamine drug substance isselected from the list consisting of cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine, and fexofenadine hydrochloride.
 7. Apharmaceutical composition comprising a compound according to claim 4,optionally together with a pharmaceutically acceptable diluent orcarrier.
 8. A process for the preparation of a compound of formula I asdefined in claim 1 that comprises the steps of: (i) (A) reacting acompound of formula II

wherein R², R³, R⁴ and R⁵ are as hereinbefore defined in claim 1 and Xis halogen, with a compound of formula III

wherein R¹ is as hereinbefore defined in claim 1; (B) reacting acompound of formula IV

wherein R², R³, R⁴ and R⁵ are as hereinbefore defined in claim 1 and Xis halogen, with a compound of formula R¹—NH₂, optionally in thepresence of a base; (C) for the preparation of compounds of formula Iwhere R¹ is a 5 or 6-membered heterocyclic ring containing nitrogen andoptionally a further hetero atom of the group consisting of nitrogen,oxygen and sulphur that is substituted by —NR⁶R⁷, reacting a compound offormula I where R¹ is a 5 or 6-membered heterocyclic ring containingnitrogen and optionally a further hetero atom of the group consisting ofnitrogen, oxygen and sulphur that is substituted by halo with a compoundof formula V

wherein R⁶ and R⁷ are as hereinbefore defined in claim 1, optionally inthe presence of a base; (D) for the preparation of compounds of formulaI where R³ is —SO₂NR⁸R⁹, reacting a compound of formula VI

wherein R², R⁴, R⁵ and X are as hereinbefore defined in claim 1 with anamine of formula VII

wherein R⁸ and R⁹ are as hereinbefore defined in claim 1; or (E) for thepreparation of compounds of formula I where one or both of R⁴ and R⁵ is—NR¹²R¹³, reacting a compound of formula I wherein R¹ and R² arehereinbefore defined, R³ is —SO₂R¹¹ or —SO₂NH₂ and one or both of R⁴ andR⁵ is halo with a compound of formula VIII

wherein R¹² and R¹³ are hereinbefore defined, optionally in the presenceof a base; or (F) for the preparation of compounds of formula I whereone or both of R⁴ and R⁵ is C₁-C₈-alkoxy substituted by a 5 or6-membered heterocyclic ring containing at least one hetero atomselected from the group consisting of nitrogen, oxygen and sulphur,reacting a compound of formula I wherein R¹ and R² are hereinbeforedefined, R³ is —SO₂R¹¹ or —SO₂NH₂ and one or both of R⁴ and R⁵ is halowith a compound of formula HO—C₁-C₈-alkyl-W where W is a 5 or 6-memberedheterocyclic ring containing at least one hetero atom selected from thegroup consisting of nitrogen, oxygen and sulphur, optionally in thepresence of a base; and (ii) recovering the resultant compound offormula I in free or salt form.